Asymmetric Neuropathies

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ASYMMETRIC NEUROPATHIES

Many asymmetric sensory-motor neuropathies are treatable.
They are a major indication for biopsies of nerve and muscle.

Mononeuritis Multiplex

Systemic disease
- Diabetes Mellitus
- Waldenström's macroglobulinemia
- Burns: Severe
Infectious
- Cytomegalovirus (in HIV)
- Leprosy
- Lyme
- Hepatitis A (Acute)
- Hepatitis C
Multifocal Demyelinating
- CIDP (Lewis & Sumner form)
- Multifocal Motor Neuropathy
Inflammatory-Immune

Multiple Intrinsic Lesions
- Neoplasm (e.g. Lymphoma)
Vascular Occlusion
- Arterial
- Cholesterol emboli
- Hyperviscosity
- Sickle cell disease
Multiple Compressive Lesions
- Trauma
- Neoplasm (Multiple)
  - Carcinomatous Meningitis
  - Schwannoma
- Liability to Pressure Palsies
- Amyloidosis
- Hemorrhage
  - Extraneural: Hemophilia
  - Intraneural: Idiopathic thrombocytopenic purpura (ITP)
Other
- Polymyalgia rheumatica: Asymptomatic
- Wartenberg's migrant sensory neuritis

Other asymmetric neuropathies

Plexopathy: Brachial; Lumbosacral
Toxic: Gold; Spanish Toxic Oil; Jelly fish
Hereditary: CMT, X-linked, Type 1; HNPP

Cytopathies

Also see: Asymmetric myopathies

Lymphoma⁵

Nerve infiltration
Widely metastatic disease
Local in nerve
CNS infiltration
Lymphoma subtypes
Angiotropic
Hodgkins
Non-Hodgkins
Lymphomatoid granulomatosis
Waldenström's macroglobulinemia
Other lymphoma-related syndromes

Infiltration of Nerve (Neurolymphomatosis)

Nerve infiltration during or after widely metastatic lymphoma
- Neoplasm associations
  - Types
    - Non-Hodgkin lymphocytic
      - Usually B-cell type
      - Pathological change in nerve in 40%
    - Acute leukemia: de novo or Transformation of Chronic myelogenous leukemia (CML)
  - Spread from: Hematogenous or Leptomeninges
  - May develop or progress when lymphoma in hematologic remission
    - Sensorimotor
    - Infiltration may be mainly endoneurial
    - ? 2° Endoneurial lymphoma not reached by treatment
- Clinical features
  - Cranial nerves
    - Common: III; V; VI; VII; Mental nerve
    - Rare: Optic nerve & chiasm
    - Syndromes: Anatomic
      - Orbital: Frontal headache; EOM paresis; Trigeminal 1 sensory loss; Proptosis
      - Parasellar: Frontal headache; EOM paresis; Trigeminal 1 sensory loss
      - Middle fossa: Facial pain; Trigeminal sensory loss± VII palsy
      - Jugular foramen: Hoarseness; Dysphagia; Lesions of cranial nerves 9 to 11
      - Occipital condyle: Localized pain; Tongue weakness (Ipsilateral)
      - Mental foramen: Numb chin
    - CSF Diagnosis of meningeal infiltration
      - Cytology: Abnormal in 80% of patients with ≥ 3 exams
      - Lactic dehydrogenase
      - β₂-microglobulin
      - Meningeal biopsy may be useful if other tests are negative
  - Peripheral nervous system syndromes
    - General: May be symmetric or asymmetric
    - Mononeuropathies
      - Most common with Non-Hodgkins lymphoma
    - Polyneuropathies
    - Motor neuropathy
      - Subacute
      - Asymmetrical & Patchy
      - Painless
      - Legs > Arms
      - Course: Benign, Self-limited
    - Radiculopathies
      - May be due to herpes zoster (VZV) infections
        
        Usually in a truncal distribution
        
        Frequency: 3–10% of lymphoma patients
      - Some patients with tumor invasion: Usually Non-Hodgkins lymphoma
      - Diagnosis: Biopsy; CSF examination
    - Plexopathies
      - Causes
        
        Infiltration by lymphoma
        
        Autoimmune disorders
        
        Radiation
      - Brachial plexus: Pain ± Lower plexus involvement
      - MRI: May show thickened or enhancing nerves or roots
    - Cauda equina syndrome: Neoplastic infiltration
    - Pathology: Axonal loss ± segmental demyelination
- Rule out: Other asymmetric neuropathies
- CSF
  - Cells: Often Increased
  - Protein: Occasionally high
Multifocal infiltrates primarily in nerve¹
- Neoplasm: T-cell lymphoma
- Clinical
  - Distribution: Asymmetric; Mononeuritis or Multiple mononeuropathies
  - Cranial & Motor-sensory nerves
  - Course: Progressive or Relapsing-Remitting
- CSF: Cells often increased
- Nerve pathology
  - Axonal loss
  - Lymphoma: Angiocentric, in vessel walls
- Treatment: Temporary improvement may occur with corticosteroids
- Muscle pathology: Angiocentric lymphoma
- Animal model: Marek's disease (T-cell lymphoma 2° oncogenic herpesvirus)

Infiltrates primarily in spinal cord & CNS¹

Angiotropic large B-cell lymphoma (Malignant angioendotheliomatosis)
- General: Proliferation of neoplastic lymphoid cells within blood vessels
- Onset: Especially 7th & 8th decade
- Neurological features
  - Presenting feature in 54%
  - CNS lesions: Multifocal; "Stroke-like"
    - Encephalopathy: Sub-acute; Dementia
    - Cortical lesions: Multi-Focal; Hemiparesis
    - Myelopathy
      - Transverse or Diffuse
      - Paraparesis; Sensory loss; Urinary dysfunction
      - Pathology: Multifocal infarction
    - Deafness
  - Peripheral nerve involvement: Occasional
    - Mononeuritis: Sudden onset
    - Mononeuritis multiplex
    - Cranial nerves: VII & Hearing loss most common; Also EOM, Trigeminal
    - Radiculopathy: Pain; Sensory loss; Weakness
- Organ involvement
  - Eye: Visual loss; Papilledema; Retinal & Choroid vessels involved
  - Skin: Most common
  - Bone marrow: with More diffuse lymphoma
  - Muscle: Asymptomatic; Intravascular
  - Adrenal: Enlargement
- Disease course
  - Untreated patients: High mortality rate; Up to 80% at 1 year
  - Treatment: May be curable with early chemotherapy (40%)
- Histopathology
  - Neoplasm features
    - Noncohesive masses of large, pleomorphic lymphoid cells
    - Location: Capillaries, venules & small arterioles
    - Neoplastic cell accumulations
      - May occlude vessels
      - Rarely extravasate into the neighboring tissues
  - Cell features
    - Nuclei: Irregular contours, Coarse chromatin, Two or multiple nucleoli
    - Cytoplasm: Moderate amounts; Basophilic; Vacuolated
    - Antigen: bcl-2 & CD-20 proteins, common; Other CD10, bcl-6 and CD5 occasional
  - Diagnosis may be made on skin, muscle or nerve biopsy
- Laboratory
  - Anemia: Mild; Hemolytic
  - Erythrocyte sedimentation rate: High
  - Serum lactate dehydrogenase: Markedly elevated
  - Coagulopathy: Occasional patients
  - CSF: Normal

Hodgkins Lymphoma

Epidemiology
- Onset: Bimodal
  - Most common: 16–34 years
  - 2nd peak: Older ages
- Frequency: 3 per 100,000 in US
- Association: Prior viral infections
  - EBV
  - HIV: Associated with virulent form
  - May be related to subtypes of Hodgkins lymphoma
Clinical
- Disease beyond lymphoreticular system: Uncommon
- Neurological complications
  - Uncommon
  - May be due to associated autoimmune syndromes: GBS
- Prognosis: 80% cure rate
- Staging of HL relatively predictive of prognosis
Pathology: Associated with Reed–Sternberg cells

Non-Hodgkins Lymphoma

Frequency of neurological involvement
- Subclinical: 35%
- Clinical: 6 to 17%
- More with: Higher disease grade; B-cell lymphoma
Disease mechanisms
- Immunosuppression
- Autoimmune
- Tumor infiltration of PNS or CNS
Associated syndromes
- Radiculopathy
- Plexopathy
- Mononeuropathy
- Polyneuropathy
- Motor neuropathy

Lymphomatoid granulomatosis

Disease features: General
- Lymphoproliferative disorder
- Angiocentric & Angiodestructive
- Due to EBV infection
Onset: Pulmonary; Brain
Neurological features
- Frequency: 30%
- Neuropathy: Rare; Associated with lymphoid infiltration
Pathology: Angiitis
Treatment: Corticosteroids; Cytotoxic agents

Lymphoma-related syndromes: Other

Paraneoplastic syndromes
GBS: Associated with Hodgkin's
Ataxia telangectasia
Monoclonal gammopathies (MGUS)
- POEMS: Castleman disease
- IgM Anti-glycolipid antibody syndromes
- Waldenström macroglobulinemia
Also see
- Myasthenia gravis: Lymphoepithelial thymoma
- Inflammatory myopathy: Hemophagocytic lymphohistiocytosis
- Diffuse infiltrative lymphocytosis syndrome (DILS): HIV infection, Not lymphoma

Cholesterol emboli

Predisposing events
- Vascular catheterization
- Anticoagulant therapy
- Aortic atherosclerosis (Ulcerative)
Polyneuropathy
- May be presenting feature
- Motor-Sensory
- Axonal
- Distribution: Symmetric, or Mononeuritis multiplex
Systemic features
- Myalgia
- Livido reticularis
- Renal & GI disorders
- Weight loss & cachexia
Lab
- Sedimentation rate: Increased
- Anemia
Pathology
- Diagnosis by muscle (92%) & nerve (epineurial vessel change) biopsy
- Cholesterol crystals (with clefts) in lumina of small arteries
Treatment: ?
Progression
- Months
- Mortality: 73%

Hemophilia A & B

Mononeuropathies in 13%
Multiple mononeuropathies in 6%
Nerve lesions more common
- Severe disease: < 1% factor VIII
- Increased age
- Lower extremity > Upper extremity
Nerves
- Femoral 10%
- Ulnar 4%
- Median 4%
- Peroneal 2%
- Sensory: Saphenous (2%); Lateral femoral cutaneous (2%)
Differential diagnosis
- Joint disorders due to hemarthrosis
- HIV
- Chronic liver disease

Idiopathic Thrombocytopenic Purpura⁶

Epidemiology: Single patient; 8th decade
Onset: Pain; Sensory loss
Clinical
- Systemic
  - Bleeding: Hematuria; Gums
  - Skin: Rash; Bruising
- Polyneuropathy
  - Weakness
    - Initial: Legs; Proximal & Distal
    - Progression: To quadriplegia
  - Sensory loss: Legs > Arms
  - Tendon reflexes: Reduced
  - Pain
  - Course: Stepwise progression over 8 months
Laboratory
- Platelets: 2000 to 4000/μl
- Bone marrow: Thrombocytopenia
- Associated neoplasm: B-cell lymphoma
- Nerve
  - Intraneural hemorrhage
    - Patchy
    - Perineurial & Subperineuial
    - Erythrocytes in Schwann cell tubes
  - Axonal loss: Chronic & Ongoing

Wartenberg's Migrant Sensory Neuritis²

Onset age: Mean 35 years; Range 4th & 5th decades
Pure sensory mononeuritis multiplex
- Course
  - Episodic; Recurrent
  - Some sensory loss improves, Other is permanent
- Sensory loss
  - Discrete areas: Involvement of individual cutaneous nerves
  - Sudden onset
  - Distribution: Legs; Arms; Trunk; Face
- Pain
  - In areas of sensory loss
  - Painful dysesthesias: Induced by limb stretch or movement
Laboratory
- Electrodiagnostic: Multifocal axon loss
- Pathology: Biopsy of affected nerve
  - Perineurial scarring
  - Chronic inflammation
  - Axonal loss & regeneration: Differential fascicular involvement
  - Endoneurial edema
  - Immunoglobulin deposition

Sickle Cell Disease⁴

Mononeuritis multiplex ³

Associated with: Sickle cell pain crisis
Frequency: Rare
Onset: Acute
Clinical
- Weakness: Lumbosacral; Asymmetric
- Pain
- Sensory loss: Legs
Course: Slow improvement
Electrodiagnostic testing
- Axonal loss
- Conduction block: Associated with acute nerve lesion
Treatment: Management of pain crises

Cranial neuropathies: Mental nerve
Toxic neuropathy
Rhabdomyolysis
- May occcur with sickle cell trait
- Associated with: Exertional heat illness; High altitude; Sudden death
- Most commonly reported in: Athletes; Military recruits
Focal myopathy
- Muscles: Quadriceps; Glutei
- Intramuscular injection of narcotics
Muscle edema: On MRI

Return to Polyneuropathy Index

References
1. Clinical Neurology and Neurosurgery 2000;101:275-279; JNNP 2001;71: 696-703
2. Muscle Nerve 2001;24:438-443
3. J Clin Neuromusc Dis 2001;3:63-69
4. Ann Neurol 2002;51:543–552
5. Muscle Nerve 2005;31:301–313
6. J Peripheral Nervous System 2007;12:286–289

12/4/2007

ASYMMETRIC NEUROPATHIES

Lymphoma5

Cholesterol emboli

Hemophilia A & B

Idiopathic Thrombocytopenic Purpura6

Wartenberg's Migrant Sensory Neuritis2

Sickle Cell Disease4

Lymphoma⁵

Idiopathic Thrombocytopenic Purpura⁶

Wartenberg's Migrant Sensory Neuritis²

Sickle Cell Disease⁴